The role of developmental control genes in human birth defects has raised the questions if orthologous genes have conserved or divergent functions and how insights gained from animal models can be applied to human. To address these questions, the investigators propose to perform a comparative genetic analysis of the functions of Gli1, Gli2 and Gli3 transcription factors that mediate hedgehog signaling. In previous studies, they have discovered or engineered mutations in human, mouse and zebrafish gli genes. In all three systems, gli mutations lead to cranio-facial and central nervous system defects. Phenotypic comparisons have suggested that these genes share some functional properties, but that their roles also differ. The long-range goal of the investigators' studies is to determine if the seemingly divergent functions of different gli genes are due to differences in Gli proteins or due to other species-specific factors. Using mouse and zebrafish as model systems, they will 1) analyze the activity of zebrafish and human Gli proteins in mouse using knock-in approaches; 2) analyze the activity of mouse and human Gli proteins in zebrafish using misexpression and complementation approaches; and 3) create animal models for human birth defects and analyze the activity of human gli mutations in zebrafish and mouse. These comparative genetic studies will allow detailed insights into the conservation and divergence of orthologous genes and will test the value of animal models in understanding human birth defects.